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Sophie’s choice: Assessing atypical Spitz tumors in the molecular era

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atypical spitz tumor
Atypical Spitz tumor category. Higher magnification reveals severe cytologic atypia. Although cells exhibit a spindled appearance typical of the Spitz nevus, they appear severely dysplastic with nuclear hyperchromasia and an immunogenic host response. (Hematoxylin-eosin stain; original magnification: ×40.)
Credit: JAAD

By Warren R. Heymann, MD
Dec. 10, 2018

One of the most challenging aspects of dermatopathology is prognosticating a so-called atypical Spitz tumor (AST) lying midway in the spectrum of a classical benign Spitz nevus and a Spitzoid melanoma. It has been 70 years since Sophie Spitz introduced the concept of benign behavior of “juvenile melanoma.” The following is the introductory paragraph of her seminal paper. Stunningly, the questions she raises are still pertinent today in the molecular era. (1)

It has become apparent over a period of years that even when a histologic diagnosis of malignant melanoma has been made in children the clinical behavior rarely has been that of a malignant tumor. The disparity in behavior of the melanomas of adults and children, despite the histologic similarity of the lesions occurring in the different age groups, is obviously a matter of fundamental importance and the following questions immediately arise: Does the histologically malignant melanoma of children differ in any structural detail from that of adults? Can the clinical behavior of these lesions be predicted from their histologic structure? What, if any, are the factors known to influence the clinical behavior? Should the melanomas of children be treated any differently from the melanomas of adults?

Aside from classical histopathology (epithelioid and spindled melanocytes with large nuclei and abundant cytoplasm, Kamino bodies, clefts, and typical mitoses), immunohistochemistry, and newer molecular techniques such as comparative genomic hybridization (CGH), polymerase chain reaction (PCR), and fluorescence in situ hybridization (FISH) offer new diagnostic perspectives in the analysis of Spitzoid lesions. (2)

Tetzlaff et al recognize that dermatopathologists are working toward a molecular-genetic classification that will assist in prognostication and potentially treatment. We are not yet at the promised land, however, the authors note the following key points: 1) Spitzoid lesions with 11p amplification and/or HRAS mutations and Spitzoid lesions with BAP1 loss and BRAF V600E mutation exhibit a typical morphology and predictably benign clinical behavior. 2) Spitzoid lesions with telomerase reverse transcriptase (TERT) promoter mutations exhibit a more aggressive clinical course; therefore, TERT promoter mutation may represent an additional marker of aggressive behavior. 3) FISH identifies Spitzoid neoplasms with increased risk for metastasis and death including those with homozygous deletion of 9p21 [corresponding to CDKN2A]. 4) Translocations involving different oncogenic kinase drivers occur across the spectrum of Spitzoid neoplasms and implicate critical oncogenic drivers that may be leveraged to inform therapeutic decisions. (3)

According to Fujimoto et al, functional kinase fusions have been identified in approximately half of Spitzoid neoplasms, including ASTs. To date, ROS1, NTRK1, NTRK3, BRAF, RET, MET, and ALK fusions have been reported in Spitzoid neoplasms. These findings are expected to enable better risk assessment and classification of these lesions. For example, the clinical behavior of ALK (anaplastic lymphoma kinase)–rearranged Spitzoid neoplasms (present in approximately 10% of these lesions) seems to be indolent, despite its potential for nodal metastasis. Therefore, the identification of ALK fusions in Spitzoid neoplasms may be important for clinical decision making. (4)

ALK alterations may characterize a significant subset of Spitzoid lesions. In a study of 78 Spitzoid plexifiorm lesions (41 Spitz nevi, 29 ASTs, and 8 Spitzoid melanomas) in which ALK immunohistochemical staining was performed, 14.6% (6/41) of Spitz nevi and 13.8% (4/29) ASTs demonstrated ALK gene alterations. All of the Spitzoid melanomas were ALK negative. FISH confirmed ALK translocation in 9 cases and amplification in 1 case. Additionally, the authors noted that of 4 ASTs demonstrating ALK fusions, 2 also carried a BRAF V600E mutation. (5)

The purpose of this exercise is to define distinct subsets of Spitzoid neoplasms that afford predictable prognostication. As more data accrues, this will be refined. For example, Rand et al reported 2 unique cases of ALK-positive ASTs with 9p21 homozygous deletions in a 9-year-old boy and a 7-year old girl, respectively. FISH analysis showed homozygous deletion of 9p21 and gain of 6p25 in both cases (and a gain of 11q13 in the girl). Their cases demonstrated the transformation of tumors produced by an activating kinase fusion gene (ALK) through secondary genetic changes, including loss of tumor suppressor activity (CDKN2A). Long-term follow up will be important to further define the behavior of these unique Spitz tumors. (6)

The following are conclusions from Sara Shalin’s outstanding review of kinase fusions in melanocytic tumors (7):

The detection of kinase fusions in approximately half of spitzoid melanocytic neoplasms has provided a framework for better understanding of spitzoid tumor development. As these fusions may be detected across the entire spectrum from benign to malignant, kinase fusions are thought to represent an early oncogenic event. Though many kinases and a variety of different binding partners have been identified, these gene fusions result in a common end point of enhanced and constitutive kinase activation leading to increased cellular growth, proliferation, and survival of tumor cells. As specific kinase fusions become more readily identified and better characterized, it will be possible to determine if specific histologic features align with the presence of particular kinase fusions or with certain fusion partners. As the catalytic domains of several of these kinases are genetically similar (for example ALK and ROS), we may find that the fusion partner drives some of the histologic or biologic differences between tumors. The biologic potential of spitzoid neoplasms is notoriously difficult to predict and, with further study of larger cohorts, the presence or absence of a kinase fusion may provide additional insight into the predicted outcome of a particular lesion. Already, kinase inhibitors are used with good effect in the treatment of other cancer types and are showing preliminary success in a subset of patients with aggressive melanocytic lesions that have a documented kinase fusion. Undoubtedly, further work in the field will continue to reveal mechanisms important for the development and growth of these tumors and will assist in the accurate diagnosis of these challenging melanocytic neoplasms.

Dr. Spitz was a brilliant pathologist. Aside from her insights in recognizing the different biologic behavior of lesions that now bear her name, she was an early advocate of the Pap smear, and also the first to describe the carcinogenicity of the aromatic amines used in the dye industry. Dr. Spitz worked until just days before her untimely death on August 11, 1956. She died at just 46 years of age of metastatic colon carcinoma. (8) Dr. Spitz chose to question standard pathologic criteria and concepts seven decades ago. It is a testament to her sagacity that the challenges she outlined are still being ardently explored.

Point to Remember: The future of prognostication for atypical Spitzoid tumors lies in the molecular realm. Utilizing kinase fusion analysis is likely to become more common in the near future.

1. Spitz S. Melanomas of childhood. Am J Pathol 1948; 24: 591-609.
2. Dika E, et al. Spitz nevi and other Spitzoid neoplasms in children: Overview of incidence data and diagnostic criteria. Pediatr Dermatol 2017; 34; 25-32.
3. Tetzlaff M, et al. Toward a molecular-genetic classification of Spitzoid neoplasms. Clin Lab Med 2017; 37: 431-448.
4. Fujimoto M, et al. A case report of atypical Spitz tumor harboring a novel MLPH-ALK gene fusion with discordant ALK immunohistochemistry results. Hum Pathol 2018; 80: 99-103.
5. Saraggi D, et al. Prevalence of ALK gene alterations among the spectrum of plexiform spitzoid lesions. J Am Acad Dermatol 2018; 79: 728-35.
6. Rand AJ, et al. Atypical ALK-positive Spitz tumors with 9p21 homzygous deletion: Report of two cases and review of the literature. J Cutan Pathol 2018; 45: 136-40.
7. Shalin SC. A review of kinase fusions in melanocytic tumors. Lab Invest 2017; 97: 158-65.
Vanderbilt University (VUMC) Historical Images and Biographies. Accessed October 6, 2018.

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